Coatings for implantable medical devices comprising hydrophilic substances and methods for fabricating the same

ABSTRACT

A segmented polyurethane and an amphiphilic random or block copolymer are disclosed. The segmented polyurethane and the amphiphilic random or block copolymer can be used for fabricating a coating for an implantable medical device such as a stent.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional application of U.S. application Ser.No. 10/746,483 filed on Dec. 24, 2003, the teaching of which isincorporated herein by reference in its entirety.

BACKGROUND

1. Field of the Invention

This invention is directed to coatings for implantable medical devices,such as drug eluting vascular stents.

2. Description of the State of the Art

Percutaneous transluminal coronary angioplasty (PTCA) is a procedure fortreating heart disease. A catheter assembly having a balloon portion isintroduced percutaneously into the cardiovascular system of a patientvia the brachial or femoral artery. The catheter assembly is advancedthrough the coronary vasculature until the balloon portion is positionedacross the occlusive lesion. Once in position across the lesion, theballoon is inflated to a predetermined size to radially compress againstthe atherosclerotic plaque of the lesion to remodel the lumen wall. Theballoon is then deflated to a smaller profile to allow the catheter tobe withdrawn from the patient's vasculature.

A problem associated with the above procedure includes formation ofintimal flaps or torn arterial linings which can collapse and occludethe conduit after the balloon is deflated. Moreover, thrombosis andrestenosis of the artery may develop over several months after theprocedure, which may require another angioplasty procedure or a surgicalby-pass operation. To reduce the partial or total occlusion of theartery by the collapse of arterial lining and to reduce the chance ofthe development of thrombosis and restenosis, a stent is implanted inthe lumen to maintain the vascular patency.

Stents are used not only as a mechanical intervention but also as avehicle for providing biological therapy. As a mechanical intervention,stents act as scaffoldings, functioning to physically hold open and, ifdesired, to expand the wall of the passageway. Typically, stents arecapable of being compressed, so that they can be inserted through smallvessels via catheters, and then expanded to a larger diameter once theyare at the desired location. Examples in patent literature disclosingstents which have been applied in PTCA procedures include stentsillustrated in U.S. Pat. No. 4,733,665 issued to Palmaz, U.S. Pat. No.4,800,882 issued to Gianturco, and U.S. Pat. No. 4,886,062 issued toWiktor.

Biological therapy can be achieved by medicating the stents. Medicatedstents provide for the local administration of a therapeutic substanceat the diseased site. In order to provide an efficacious concentrationto the treated site, systemic administration of such medication oftenproduces adverse or toxic side effects for the patient. Local deliveryis a preferred method of treatment in that smaller total levels ofmedication are administered in comparison to systemic dosages, but areconcentrated at a specific site. Local delivery thus produces fewer sideeffects and achieves more favorable results. One proposed method formedicating stents involves the use of a polymeric carrier coated ontothe surface of a stent. A solution which includes a solvent, a polymerdissolved in the solvent, and a therapeutic substance dispersed in theblend is applied to the stent. The solvent is allowed to evaporate,leaving on the stent surface a coating of the polymer and thetherapeutic substance impregnated in the polymer. Once the stent hasbeen implanted at the treatment site, the therapeutic substance has asustained release profile from the polymer.

Although local administration of therapeutic agents via stents has shownfavorable results in reducing restenosis, improvements can be made tostent coatings. The controlled release of hydrophilic drugs, peptides,proteins, oligonucleotides, plasmids and DNA can be difficult withpolymeric coatings due to the osmotic pressure from water absorptiongenerated by the hydrophilicity of the agent. Upon penetration of waterinto the coating, the permeability of the coating for the hydrophilicdrug is significantly increased, resulting in the elution of the drug ata therapeutically ineffective rate. Accordingly, it is desirable toprovide a coating that includes a hydrophobic fraction to minimize waterabsorption. Moreover, hydrophobic polymers tend to adhere better tostent substrates and the mechanical integrity of high molecular weighthydrophobic polymers is typically superior. If the matrix is toohydrophobic, however, the polymer may have a poor solubility in solventsystems which are required to dissolve the drug to form a homogenouscoating solution. The hydrophilic drug will rapidly phase separate in anuncontrolled manner resulting in drug aggregation. Drug aggregationproduces unpredictable and variable release rate profiles. The result isa drug coating on a stent that is irreproducible such that each coatedstent will have variable drug content and distribution with differentrelease profiles. Particles of hydrophilic drugs also weaken ahydrophobic coating and cause local areas of high swelling. As amanufacturing stand point, replication of the same coating with similardrug distribution and release rate profile is desired.

A hydrophilic fraction in a coating is needed to make the agent morecompatible in the coating, decrease the size of the drug aggregation,and minimize variability of the release rate of the drug from thecoating. Hydrophilicity is important for both solution stability and theequal distribution of the drug in the coating. If, however, the coatingis highly hydrophilic, the stent coating will rapidly absorb water. Therapid absorption of water plasticizes the polymer, resulting in adepression of the glass transition temperature to produce a softgel-like coating. The mechanical properties of a plasticized gel-likereservoir are insufficient for wet expansion. The polymer can tear uponexpansion and produce a coating with undesirable defects. Excessivewater swelling not only weakens the polymer, but also increases thediffusivity of the drug, resulting in loss of release control.

The embodiments of the present invention address these concerns as wellas others that are apparent by one having ordinary skill in the art.

BRIEF DESCRIPTION OF DRAWINGS

FIGS. 1A-1F, 4, and 5 are microphotographs of stents coated according toembodiments of the present invention after simulated in vitro testing.

FIGS. 2, 3, and 6 are graphs illustrating the rate of release of a drugfrom stents coated according to embodiments of the present invention.

SUMMARY

A medical article is provided, the medical article comprises animplantable substrate and a polymer coating disposed at least on aportion of the substrate, the coating including a segmented polyurethanecomprising a soft segment and a hard segment. Examples of segmentedpolyurethanes that can be used include poly(urethane-urea), poly(etherurethane) and poly(carbonate urethane).

A medical article is provided, the medical article comprises animplantable substrate and a polymer coating disposed at least on aportion of the substrate, the coating including an amphiphilic copolymercomprising at least one hydrophobic moiety and at least one hydrophilicmoiety. Examples of amphiphilic polymers that can be used includeacrylic copolymers, such as a random copolymer or a block copolymer, forexample an ABA block copolymer and an AB block-copolymer. Theamphiphilic block-copolymer can be a product of living free radicalcopolymerization of plurality of monomers with initiation-transfer agenttermination of the living macro-chains.

The coating can further include a hydrophilic therapeutic agent, such asa water soluble drug, for example cyclic-RGD peptide, poly(L-arginine),poly(D-arginine), poly(D,L-arginine), poly(L-lysine), poly(D-lysine),poly(δ-guanidino-α-aminobutyric acid), a racemic mixture ofpoly(L-arginine) with poly(D-arginine), elastin mimetic polypeptides,and blends thereof.

DETAILED DESCRIPTION 1. Terms and Definitions

The term “random copolymer” is defined in accordance with terminologyused by the International Union of Pure and Applied Chemistry (IUPAC).The IUPAC defines a random copolymer as a copolymer consisting ofmacromolecules in which the probability of finding a given monomericunit at any given site in the chain is independent of the nature of theadjacent units. In a random copolymer, the sequence distribution ofmonomeric units follows Bernoullian statistics.

The term “block-copolymer” is also defined in accordance with theterminology used by the International Union for Pure and AppliedChemistry (IUPAC). “Block-copolymer” refers to a copolymer containing alinear arrangement of blocks. The block is defined as a portion of apolymer molecule in which the monomeric units have at least oneconstitutional or configurational feature absent from the adjacentportions.

The term “AB block-copolymer” is defined as a block-copolymer havingmoieties A and B arranged according to the general formula-{[A-]_(m)-[B]_(n)}-_(x), where each of “m,” “n,” and “x” is a positiveinteger, and m≧2, and n≧2.

The term “ABA block-copolymer” is defined as a block-copolymer havingmoieties A and B arranged according to the general formula-{[A-]_(m)-[B-]_(n)-[A]_(p)}-_(x), where each of “m,” “n,” “p,” and “x”is a positive integer, and m≧2, and n≧2, and p≧2.

The term “ABC block-copolymer” is defined as a block-copolymer havingmoieties A, B, and C arranged according to the general formula-{[A-]_(m)-[B-]_(n)-[C]_(p)}_(x)- where each of “m,” “n,” “p,” and “x”is a positive integer, and m≧2, and n≧2, and p≧2.

The blocks of the block-copolymers need not be linked on the ends, sincethe values of the integers determining the number of blocks are such asto ensure that the individual blocks are usually long enough to beconsidered polymers in their own right. Accordingly, the ABA blockcopolymer can be named poly A-block-co-poly B block-co-poly Ablock-copolymer, the ABC block copolymer can be named polyA-block-co-poly B block-co-poly C block-copolymer and the AB blockcopolymer can be named poly A-block-co-poly B block-copolymer. Blocks“A,” “B,” and “C,” typically, larger than three-block size, can bealternating or random.

The term “segmented polyurethanes” is defined as polyurethanes having asoft segment and a hard segment.

The term “moiety” is defined as a portion of a complete structure of acopolymer, the portion to include at least 2 atoms joined together in aparticular way. The term “moiety” includes functional groups and/ordiscreet bonded residues that are present in the macromolecule of acopolymer. The term “moiety” as used herein is inclusive of individualunits in the random copolymers. The term “moiety” as used herein is alsoinclusive of entire polymeric blocks in the block-copolymers.

The term “poly(urethane-urea)” is defined as a polymer having both theurethane moiety (—NH—C(O)—O—) and the urea moiety (—NH—C(O)—NH—).

The term “acrylic copolymers” is defined as copolymers having at leastone unit derived from either acrylic acid CH₂═CH—COOH or frommethacrylic acid CH₂═C(CH₃)—COOH.

A polymer is classified as “hydrophilic” or “hydrophobic” depending onthe value of the polymer's Hildebrand solubility parameter. The term“Hildebrand solubility parameter” is defined as a parameter δ indicatingthe cohesive energy density of a substance. The δ parameter isdetermined as follows:δ=(ΔE/V)^(1/2)where δ is the solubility parameter, (cal/cm³)^(1/2); ΔE is the energyof vaporization, cal/mole; and V is the molar volume, cm³/mole.

The terms “hydrophilic moiety” and “hydrophobic moiety” is each definedas a moiety capable of forming a hydrophilic or a hydrophobichomopolymer, respectively. In other words, if a homopolymer containingexclusively a hydrophilic moiety were synthesized, the homopolymer wouldbe hydrophilic; if a homopolymer containing exclusively a hydrophobicmoiety were synthesized, the homopolymer would be hydrophobic.

The term “amphiphilic copolymers” is defined as copolymers the structureof which includes both hydrophilic and hydrophobic moieties.

The term “water soluble drug” is defined as a drug which can form astable, clear aqueous solution containing, at equilibrium, not less thanabout 5 mass % of the drug. The drug is defined as a “small-moleculedrug” if the molecular of the active agent in the drug is less thanabout 10,000 Daltons.

2. Embodiments of the Invention

A coating for an implantable medical device, such as a stent, accordingto embodiments of the present invention, can include any one or all ofthe following three layers:

(a) a primer layer;

(b) a drug-polymer layer (also referred to as “reservoir” or “reservoirlayer”) or alternatively a polymer free drug layer; and/or

(c) a topcoat layer.

Each layer of the stent coating can be formed on the stent by dissolvingthe polymer or a blend of polymers in a solvent, or a mixture ofsolvents, and applying the resulting polymer solution on the stent byspraying or immersing the stent in the solution. After the solution hasbeen applied onto the stent, the coating is dried by allowing thesolvent to evaporate. The process of drying can be accelerated if thedrying is conducted at an elevated temperature.

To incorporate a drug into the reservoir layer, the drug can be combinedwith the polymer solution that is applied onto the stent as describedabove. Alternatively, to fabricate a polymer free drug layer, the drugcan be dissolved in a suitable solvent or mixture of solvents, and theresulting drug solution can be applied on the stent by spraying orimmersing the stent in the drug solution.

Instead of introducing the drug as a solution, the drug can beintroduced as a colloidal system, such as a suspension in an appropriatesolvent phase. To make the suspension, the drug can be dispersed in thesolvent phase using conventional techniques used in colloid chemistry.Depending on a variety of factors, e.g., the nature of the drug, thosehaving ordinary skill in the art can select the solvent to form thesolvent phase of the suspension, as well as the quantity of the drug tobe dispersed in the solvent phase. The suspension can be mixed with apolymer solution and the mixture can be applied on the stent asdescribed above. Alternatively, the drug suspension can be applied onthe stent without being mixed with the polymer solution.

The drug-polymer layer can be applied directly onto at least a part ofthe stent surface to serve as a reservoir for at least one active agentor a drug which is incorporated into the reservoir layer. The optionalprimer layer, free of any drugs, can be applied between the stent andthe reservoir to improve the adhesion of the reservoir to the stent. Thetopcoat layer can be applied over at least a portion of the reservoirlayer to serve as a rate limiting membrane. The topcoat layer can beessentially free from any active agents or drugs.

According to embodiments of the present invention, the drug-polymerlayer can contain a water-soluble, small molecule drug, or a blend ofmore than one of such drugs. The mass ratio between the drug and thepolymer in the drug polymer layer can be between about 1:10 and about1:3, such as between about 1:9 and about 1:4, for example, about 1:6.

A. Drugs

Water-soluble, small molecule drugs that can be incorporated in thedrug-polymer layer include proteins, peptides, biologically activecompounds conjugated to peptides, anti-inflammatory, anti-proliferative,or antimicrobial drugs. In one embodiment, the drugs include cyclic-RGD(c-RGD) peptide, poly(L-arginine), poly(D-arginine), poly(D,L-arginine),poly(L-lysine), poly(D-lysine), poly(δ-guanidino-α-aminobutyric acid), aracemic mixture of poly(L-arginine), poly(D-arginine), and elastinmimetic polypeptides. The term “cyclic RGD” refers to a peptide that isa product of condensation of arginine (amino acid R), glycine(aminoacetic acid or amino acid G), and aspartic acid (amino acid D),the peptide having a cyclic structure.

The terms “poly(L-arginine),” “poly(D-arginine),” “poly(D,L-arginine)”are intended to include L-, D-, and/or D,L-arginine in both itspolymeric and oligomeric form. Polymers and/or oligomers of L-, D-,and/or D, L-arginine that can be used comprise a plurality of repeatingmonomeric amino acid units connected with peptide bonds, each unitincluding 1-guanidinopropyl radical having the structure—CH₂—CH₂—CH₂—NH—C(NH₂)═NH. In one embodiment, a heptamer (R7) (p=7), ora nonamer (R9) (p=9) of L-arginine, can be used.

Elastin mimetic polypeptides are protein pentamers comprising a numberof amino acids and having the formula-[(V/I)-P-G-Xaa-G]₅-,  (I)where V is valine (2-amino-3-methylbutyric acid), I is isoleucine(2-amino-3-methylvaleric acid), P is proline [(S)-2-pyrrolidinecarboxylic acid], G is glycine (aminoacetic acid), and Xaa is an aminoacid which is valine in the first four repeating units and eitherisoleucine or lysine [(S)-2,6-diaminohexanoic acid or K] in the fifthrepeating unit. The abbreviation “V/I” signifies that either valine orisoleucine, but not both, can be present.

B. Polymers

The stent coating, in which a water-soluble, small molecule drugdescribed above is incorporated, includes at least one polymer. Thepolymer(s) that can be used include (1) segmented polyurethanes, e.g.,segmented poly(urethane ureas), or (2) acrylic copolymers, as discussedbelow.

1. Segmented Polyurethanes

According to embodiments of present invention, the soft segment ofsegmented polyurethanes that can be used for making the stent coatingscan be derived from a polyol and the hard segment can be derived from anisocyanate. The soft segment provides the polyurethane with theproperties of an elastomer. Thus, the soft segment can serve to preventor at least reduce the cracking of the coating. The hard segmentprovides the stent coating with mechanical strength. In addition,segmented polyurethanes that can be used possess a high degree ofhydrogen bonding to provide good adhesion of the stent coating to thestent.

Various types of segmented polyurethanes that can be used for making thestent coatings include poly(urethane ureas). Formula (II) demonstrates abasic structure of an exemplary class of segmented poly(urethane ureas)based on an aromatic diisocyanate.

As can be seen from formula (II), the hard segment includes both theurethane moiety (—NH—C(O)—O—) and the urea moiety (—NH—C(O)—NH—); thesoft segment is derived from a low molecular weight poly(ethyleneglycol) (x is about 40).

One example of a segmented poly(urethane urea) that can be used includesBIOSPAN polymers available from Polymer Technology Group of Berkeley,Calif. BIOSPAN is a trade name of a group of polyurethane elastomersbased on an aromatic poly(ether urethane urea) with a soft segmentderived from poly(tetramethylene oxide) and a hard segment derived fromdiphenylmethane diisocyanate. To fabricate a BIOSPAN polymer, mixeddiamines can further be used as chain extenders.

In addition to, or instead of, the BIOSPAN polymers, alternativesegmented poly(urethane ureas) can be used. In the alternativepoly(urethane ureas), a hard segment is derived from a diisocyanate, asoft segment is derived from a polyol, and diamines are used as chainextenders. Examples of diisocyanates that can be used include aromaticisocyanates (e.g., 2,4-toluene diisocyanate), cycloaliphatic isocyanates(e.g., 1,4-cyclohexane diisocyanate, methylene dicyclohexyldiisocyanate, or 1,6-hexamethylene diisocyanate), and aliphaticdiisocyanates (e.g., 1,6-diisocyanato hexane or 1,6-diisocyanatododecane).

Examples of polyols that can be used include poly(ethylene glycol),poly(propylene glycol), poly(tetramethylene glycol), poly(ethyleneglycol-co-propylene glycol), and PLURONIC products. PLURONIC is a tradename of a group of surfactants based on poly(ethylene oxide-co-propyleneoxide). PLURONIC products are available from BASF Corp. of Parsippany,N.J. Examples of chain-extending diamines include 1,4-butanediamine,1,5-pentanediamine, 1,3-diaminocyclohexane, 1,4-diaminocycloxexane, andmixtures thereof.

In addition to, or instead of, poly(urethane ureas), alternatively,other types of segmented polyurethanes can be used to fabricate stentcoatings. Examples of the alternative segmented polyurethanes that canbe used include poly(ether urethanes) and poly(carbonate urethanes). Ifpoly(ether urethanes) are used in the drug-polymer layer of the stentcoating, it may be necessary to use a primer layer to improve adhesionof the stent coating to the stent. Examples of particular kinds ofpoly(ether urethanes) that can be utilized include PELLETHANE andTECOFLEX. PELLETHANE is a trade name of a family of thermoplasticpolyurethane elastomers available from Dow Chemical Co. of Midland,Mich. TECOFLEX is a trade name of a family of thermoplastic polyurethaneelastomers available from Thermedics Polymer Products Co. of Wilmington,Mass.

In addition to a segmented polyurethane and a drug, a drug-polymer layerof a stent coating can optionally include some stabilizing additivessuch as poly(methacrylates), and/or antioxidants such as vitamin E.Also, in order to increase the rate of release of a drug from the stentcoating, pore forming agents can be blended with a segmentedpolyurethane in the drug-polymer layer. Examples of pore forming agentsthat can be used include low molecular weight poly(ethylene glycol)(e.g., having molecular weight of about 3,400 Daltons), poly(N-vinylpyrrolidone), sugars, and inorganic salts (e.g., sodium phosphate).

2. Acrylic Copolymers

According to embodiments of the present invention, acrylic copolymerscan be used for making the stent coatings include both random copolymersand block-copolymers. The acrylic copolymers that can be used can beamphiphilic copolymers and can include at least one hydrophobic moietyand at least one hydrophilic moiety. For example, in case of randomcopolymers, some constituent units of the copolymers can include ahydrophobic moiety while other constituent units can include ahydrophilic moiety. Examples of block-copolymers that can be usedinclude AB-, ABA, and ABC block-copolymers.

In case of AB copolymers, either moiety A or moiety B can be ahydrophobic moiety, and the other moiety can be a hydrophilic moiety. Incase of ABA block-copolymers, the central B-block can be hydrophobic,and the terminal A blocks can be hydrophilic, or vice versa. In case ofABC block copolymers, either moiety A, B, or C, or any two of A, B, andC can be a hydrophobic moiety or moieties, while the remaining moiety ormoieties can be a hydrophilic moiety or moieties, or vice versa.

Whichever moiety in the amphiphilic copolymer has lower Hildebrand δvalue compared to the δ value of the other moiety in the copolymer isdesignated as a hydrophobic moiety, and the moiety with higher δ valueis designated as a hydrophilic moiety. If more than two moieties areused in the copolymer, then each can be ranked in order of its δ value.For the practice of the present invention, the value of δ of aparticular moiety is inconsequential for classifying a moiety ashydrophobic or hydrophilic. In one embodiment, the δ value defining theboundary between the hydrophobic and hydrophilic moieties of thecopolymer can be about 10 (cal/cm³)^(1/2). According to this exemplaryembodiment, the hydrophobic moieties of the copolymer can have the δvalue below 10 (cal/cm³)^(1/2), and the hydrophilic moieties can havethe δ value of about 10 (cal/cm³)^(1/2) or higher.

If random copolymers comprising moieties A and B are used, in themacromolecules of the random AB copolymer moieties A and B aredistributed along the chains randomly. The random acrylic copolymers canbe obtained by common synthetic methods, for example, by radicalcopolymerization of acrylic monomers in bulk, solution, suspension, oremulsion, in the presence of suitable initiators. Examples of standardinitiators of radical polymerization can be used include2,2-dimethoxy-2-phenol acetophenone. Benzophenone can be optionallyadded to 2,2-dimethoxy-2-phenol acetophenone as a photosensitizer.

If the block-copolymers are used, moieties A, B, and C can be arrangedas A, B and C polymeric blocks, as illustrated by formula (III):

wherein:

(a) m, n, p are all integers, wherein m>0, n>0, and p≧0;

(b) X, Y, and Z is each, independently, hydrogen or an alkyl group, forexample, methyl group; and

(c) R, R₁, and R₂ is each, independently, a straight-chained or branchedsubstituted or unsubstituted alkyl group, or substituted orunsubstituted aryl group, where the substitutents in the aryl groupinclude halogens, hydroxyl, carboxyl or amino groups.

The polymer represented by formula (III) can be an AB block-copolymer,an ABA block-copolymer, or an ABC block-copolymer. For example, if p=0,the polymer of formula (III) is an AB block-copolymer. If p≠0, thepolymer of formula (IV) is either an ABA block-copolymer or an ABCblock-copolymer. It is an ABA block-copolymer if, when p≠0, both X=Z andR=R₂. It is an ABC block-copolymer, if, when p≠0, either X≠Z, or R≠R₂,or both X≠Z, and R≠R₂.

The structure of a random copolymer is generally similar to thestructure of formula (III), except the A-, B-, and C-units in the randomcopolymer are distributed randomly and not in blocks.

One synthetic method that can be used to obtain the block copolymersrepresented by formula (III), is the method of living free radicalcopolymerization with initiation-transfer agent termination of theliving macro-chains (the inferter process). The inferter processutilizes an initiator capable of undergoing thermal and/or photolyticfree radical decomposition. Examples of suitable initiators includebenzyl-N,N-diethyldithiocarbamate (BDC) orp-xylylene-N,N-diethyldithiocarbamate (XDC). BDC is a derivative oftoluene and has the formula

XDC is a derivative of p-xylene and has the formula

The BDC and XDC initiators can be prepared synthetically. To synthesizeBDC, sodium N,N-diethyldithiocarbamate can be combined with benzylbromide in an anhydrous methanol solution. The ratio between sodiumN,N-diethyldithiocarbamate and benzyl bromide can be close to equimolar.The mixture can be stirred for about 24 hours at about room temperatureto yield BDC. The process can be completed by evaporating methanol at areduced pressure and vacuum distillation. The synthesis of XDC issimilar, except instead of benzyl bromide, α,α-dibromo-p-xylene is used,and the molar ratio between sodium N,N-diethyldithiocarbamate andα,α-dibromo-p-xylene can be about 1:2.3. The product of reaction is XDCwhich can be purified by re-crystallization in methanol.

One possible path of the process of decomposition of an initiator isshown for BDC by scheme (IV):

As a result of decomposition of BDC, two types of radicals aregenerated: the benzylic radical (species A), which undergoesfree-radical addition to a monomer molecule initiating polymerization,and the dithiocarbamate radical, which terminates by heterolytic radicalcombination. One possible path of polymerization is shown by reactionschemes (V) and (VI) below.

In reaction (VI), radical A serves as a free-radical initiator reactingwith the monomer 1 creating reactive species (2). The reactive species(2) can further react with radical B acting as a transfer agentterminator, as shown by reaction (VI). The reactive species (3) shown byreaction (VI) below, in the presence of monomer and light will undergoheterolytic cleavage yielding the reactive polymer chain and the chaintransfer agent, species B. The process is propagated until monomer (1)has been consumed:

Following the completion of polymerization, monomer (1) can be added andthe process analogous to the process described by reactions (V)-(VII)can be repeated, resulting in formation of an AB block copolymer. If adifunctional or multifunctional inferter is used, an ABA block-copolymercan be obtained in a similar fashion.

The hydrophobic moiety forming the random or block copolymer (B-blocksin formula IV) can be derived from unsaturated monomers, for example,unsubstituted or substituted acrylates or vinyl monomers having ageneral formula CH₂═CX-M, where X is hydrogen or methyl and M is asubstituted or unsubstituted aryl group or an ester group O═C(OR)—, (Ris an alkyl or aryl).

Some monomers that can be used to form the hydrophobic moiety aresummarized in Table 1. Other monomers described by the formula CH₂═CX-Mcan be used, if desired.

TABLE 1 No. Monomer, CH₂═CX—M Abbreviation X M 1 Methyl methacrylate MMACH₃

2 Ethyl methacrylate EMA CH₃

3 n-Butyl methacrylate BMA CH₃

4 Lauryl methacrylate LMA CH₃

5 Styrene (vinyl benzene) ST H —C₆H₅

The hydrophilic moiety forming the random or block copolymer can bederived from unsaturated monomers, for example, unsubstituted orsubstituted acrylates or vinyl monomers having a general formulaCH₂═CX-M, where X is hydrogen or methyl and M is a substituted orunsubstituted aromatic group or an ester group O═C(OR)—(R is hydrogen ora hydroxyalkyl group). Some monomers that can be used to form thehydrophilic moiety are summarized in Table 2.

TABLE 2 No. Monomer, CH₂═CX—M Abbreviation X M 1 2-hydrohyethylmethacrylate HEMA CH₃

2 Acrylic acid AA H

3 Methacrylic acid MAA CH₃

4 N-vinyl pyrrolidone VP H

5 Poly(ethylene glycol)-acrylate PEGA H

Monomers described by the formula CH₂═CX-M other than those shown inTable 2 can be also used, if desired, for example, 2-methacryloylethylphosphoryl choline, phosphoryl choline methacrylate,2-acrylamido-2-methyl-1-propanesulfonic acid, 3-sulfopropyl acrylate,3-sulfopropyl methacrylate, vinylsulfonic acid, 4-styrenesulfonic acidand 3-allyloxy-2-hydroxypropanesulfonic acid.

Optionally, after the acrylic random or block-copolymers have beensynthesized, they can be mixed with stabilizing additives, and/orantioxidants, and/or pore forming agents described above.

The segmented polyurethanes and the acrylic random and block-copolymersdescribed above can be used for making any layer of the stent coating.Both the segmented polyurethanes and the acrylic random andblock-copolymers described above can be used alone or in combinationwith other suitable polymers to make the coating. In other words, thecopolymer can be blended or layered with other polymers.Poly(ethylene-co-vinyl alcohol) (EVAL) is one example of a polymer thancan be employed. EVAL is a product of hydrolysis of ethylene-vinylacetate copolymers and may also be a terpolymer including up to 5 molar% of units derived from styrene, propylene and other suitableunsaturated monomers.

Representative examples of other suitable polymers includepoly(hydroxyvalerate), poly(L-lactic acid), polycaprolactone,poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester,polyanhydride, poly(glycolic acid), poly(D,L-lactic acid), poly(glycolicacid-co-trimethylene carbonate), poly(glycerol-sebacate),polyphosphoester, polyphosphoester urethane; poly(amino acids),cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate),co-poly(ether-esters) (e.g. PEO/PLA), polyalkylene oxalates,polyphosphazenes, biomolecules (such as fibrin, fibrinogen, cellulose,starch, collagen and hyaluronic acid), polyurethanes other than thosedescribed above, silicones, polyesters, polyolefins, polyisobutylene andethylene-alphaolefin copolymers, acrylic polymers and copolymers otherthan those described above, vinyl halide polymers and copolymers (suchas polyvinyl chloride), polyvinyl ethers (such as polyvinyl methylether), polyvinylidene halides (such as polyvinylidene fluoride andpolyvinylidene chloride), polyacrylonitrile, polyvinyl ketones,polyvinyl aromatics (such as polystyrene), polyvinyl esters (such aspolyvinyl acetate), copolymers of vinyl monomers with each other andolefins (such as ethylene-methyl methacrylate copolymers,acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetatecopolymers), polyamides (such as Nylon 66 and polycaprolactam), alkydresins, other polycarbonates, polyoxymethylenes, polyimides, polyethers,epoxy resins, other polyurethanes, rayon, rayon-triacetate, cellulose,cellulose acetate, cellulose butyrate, cellulose acetate butyrate,cellophane, cellulose nitrate, cellulose propionate, cellulose ethers,soluble fluorinated polymers and carboxymethyl cellulose.

The embodiments of the present invention are described in connectionwith a stent, e.g., balloon expandable or self-expandable stents;however, other implantable medical devices can also be coated with thedescribed block copolymers. Examples of such implantable devices includestent-grafts, grafts (e.g., aortic grafts), artificial heart valves,cerebrospinal fluid shunts, pacemaker electrodes, and endocardial leads(e.g., FINELINE and ENDOTAK, available from Guidant Corp. of SantaClara, Calif.). The underlying structure of the device can be ofvirtually any design. The device can be made of a metallic material oran alloy such as, but not limited to, cobalt chromium alloy (ELGILOY),stainless steel (316L), “MP35N,” “MP20N,” ELASTINITE (Nitinol),tantalum, nickel-titanium alloy, platinum-iridium alloy, gold,magnesium, or combinations thereof. “MP35N” and “MP20N” are trade namesfor alloys of cobalt, nickel, chromium and molybdenum available fromStandard Press Steel Co. of Jenkintown, Pa. “MP35N” consists of 35%cobalt, 35% nickel, 20% chromium, and 10% molybdenum. “MP20N” consistsof 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum. Devicesmade from bioabsorbable or biostable polymers could also be used withthe embodiments of the present invention.

Embodiments of the present invention are further illustrated by thefollowing examples.

Example 1 Synthesis of an ABA Block Copolymer #1 (PSPMA-PBMA-PSPMA)

As a first step, a monomer BMA was dissolved in 2-butanone (also knownas methyl ethyl ketone) and an initiator XDC was added. The amounts ofcomponents are summarized in Table 3.

TABLE 3 Experimental amount of the component No. Component mmol g 1 BMA140.700 19.98 2 2-butanone — 59.41 3 XDC 0.287 0.1151

The solution of BMA and XDC in 2-butanone was placed into a borosilicatevial, purged with dry nitrogen for about 30 minutes and the vial wassealed. The contents of vial were subjected to UV radiation at awavelength within a range of between about 310 nm and about 400 nm, forabout 12 hours. The vial was then opened and the contents were addeddropwise to ethanol cooled to a temperature of about −76° C. As aresult, poly(butylmethacrylate)-XDC (PBMA-XDC) was precipitated. Theprecipitate was collected using a vacuum funnel and vacuum-dried.

As a second step, PBMA-XDC obtained as described above was combined with3-sulfopropylmethacrylate (SPMA) and aqueous 2-butanone in the amountsshown in Table 4.

TABLE 4 No. Component Weight fraction Amount, grams 1 PBMA-XDC 0.7510.00 2 3-sulfopropylmethacrylate 0.25 3.33 3 2-butanone/water — 40.00

The blend of PBMA-XDC, 3-sulfopropylmethacrylate, and 2-butanone wasplaced into a borosilicate vial, purged with dry nitrogen for about 10minutes and the vial was sealed. The contents of vial were subjected toUV radiation at a wavelength within a range of between about 310 nm andabout 400 nm, for about 12 hours. The vial was then opened and thecontents were added dropwise to water and vigorously stirred causingprecipitation of a poly(3-sulfopropylmethacrylate)-block-poly(butylmethacrylate)-block-poly(3-sulfopropylmethacrylate)-XDC.The precipitate was collected using a vacuum funnel and vacuum-driedfollowed by hydrolysis in the presence of potassium ethoxide to removethe N,N-diethyl-dithiocarbamate functionality. As a result of thedescribed process, an ABA block copolymer,poly(3-sulfopropylmethacrylate)-block-poly(butylmethacrylate)-block-poly(3-sulfopropylmethacrylate), was precipitated, the ABA block copolymer having thestructure (VII):

The molecular weight of the PBMA-based mid-blocks (B blocks) was about66,700 Daltons as measured by the method of gel-permeationchromatography (GPC) corresponding to the value of n˜470, and themolecular weight of the poly(3-sulfopropylmethacrylate)-based end blocks(A blocks) was about 11,100 Daltons, corresponding to values of ˜54 andp˜54.

Example 2 Synthesis of an ABA Block Copolymer #2 (PMAA-PBMA-PMAA)

As a first step, PBMA-XDC can be synthesized as described in Example 1.As a second step, PBMA-XDC can be combined in a vial with methacrylicacid (MAA) and 2-butanone in the amounts shown in Table 5.

TABLE 5 Theoretical amount Experimental amount of the component of thecomponent No. Component mmol g mmol g 1 PBMA-XDC 0.016 2.50 0.013 2.03 22-butanone — 12.40 — 10.19 3 Methacrylic acid 7.20 0.625 9.10 0.78425

The blend of PBMA-XDC, methacrylic acid and 2-butanone can be subjectedto UV radiation at a wavelength within a range of between about 310 nmand about 400 nm, for about 32.5 hours. The vial can be then opened, thesolvent can be removed by evaporation, the contents can be dissolved intetrahydrofuran and the solution can be added dropwise to water andvigorously stirred causing precipitation of a poly(methacrylicacid)-block-poly(butylmethacrylate)-block-poly(methacrylic acid)-XDC.The precipitate can be collected using a vacuum funnel and vacuum-driedfollowed by hydrolysis in the presence of a strong base to remove XDC.As a result of the described process, an ABA block copolymer,poly(methacrylic acid)-block-poly(butylmethacrylate)-block-poly(methacrylic acid), can be precipitated, the ABAblock copolymer having the general formula (VIII):

The molecular weight of the BMA-based mid-blocks (B blocks) inblock-copolymer (VIII) can be about 85,000 Daltons as measured by GPCcorresponding to the value of n˜599, and the molecular weight of themethacrylic acid-based end blocks (A blocks) can be about 10,020Daltons, corresponding to values of m˜116 and p˜116, resulting in molarratio between units derived from MAA and BMA of about 14:72:14.

Example 3 Synthesis of an ABA Block Copolymer #3(PEG-Acrylate-PBMA-PEG-Acrylate)

As a first step, PBMA-XDC was synthesized as described in Example 1. Asa second step, PBMA-XDC was combined in a vial with acryloylpoly(ethylene glycol) (acryloyl-PEG) and 2-butanone in the amounts shownin Table 6.

TABLE 6 Theoretical amount Experimental amount of the component of thecomponent No. Component mmol g mmol g 1 PBMA-XDC 0.0064 1.00 0.0059 0.932 2-butanone — 12.40 — 10.08 3 Acryloyl-PEG 0.625 0.25 0.778 0.29176Acryloyl-PEG is a product of esterification of acrylic acid by PEG andhas a formula (IX):

A low molecular weight acryloyl-PEG oligomer with the number-averagedmolecular weight (M_(n)) of about 375 was used, corresponding to thevalue “x” in formula of (X) of about 7. The blend of PBMA-XDC,acryloyl-PEG and 2-butanone was subjected to UV radiation as describedin Example 2, for about 43 hours. The vial was then opened, the contentswere added dropwise to water and vigorously stirred at a temperature ofabout 70° C. for about 2 hours, causing evaporation of 2-butanone andforming a suspension ofpoly(acryloyl-PEG-block-butylmethacrylate-block-acryloyl-PEG)-XDC. Thesuspension was cooled to the room temperature and the precipitate wascollected using a vacuum funnel and vacuum-dried followed by hydrolysisin the presence of a strong base to remove XDC. As a result of thedescribed process, an ABA block copolymer,poly(acryloyl-PEG)-block-poly(butylmethacrylate)-block-poly(acryloyl-PEG),was precipitated, the ABA block copolymer having the general formula(X):

Example 4 Synthesis of an ABA Block Copolymer #4 (PHEMA-PBMA-PHEMA)

As a first step, PBMA-XDC was synthesized as described in Example 1. Asa second step, PBMA-XDC was combined in a vial with 2-hydroxyethylmethacrylate (HEMA) and 2-butanone in the amounts shown in Table 7.

TABLE 7 Theoretical amount Experimental amount of the component of thecomponent No. Component mmol g mmol g 1 PBMA-XDC 0.016 2.50 0.013 2.03 22-butanone — 12.40 — 10.19 3 HEMA 3.85 0.50 3.13 0.406

The blend of PBMA-XDC, HEMA and 2-butanone was subjected to UV radiationat a wavelength within a range of between about 310 nm and about 400 nm,for about 5 hours at room temperature (about 25° C.). The vial was thenopened, about 1 ml of 1M solution of tert-butoxide in tetrahydrofuranwas added, and the solvent was removed by evaporation. The contents ofthe vial were then dissolved in 100 ml of a blend of dimethylacetamideand water. The mass ratio between dimethylacetamide and water in theblend was about 1:1. The solution was then dialyzed against water forabout 48 hours, and then dialyzed against methanol for about 24 hours.As a result of the described process, an ABA block copolymer,poly(2-hydroxyethylmethacrylate)-block-poly(butylmethacrylate)-block-poly(2-hydroxyethylmethacrylate), was precipitated, the ABA block copolymer having thegeneral formula (XI):

The molecular weight of the PBMA-based mid-blocks (B blocks) inblock-copolymer (XI) was about 85,000 Daltons as measured by GPCcorresponding to the value of n˜599, and the molecular weight of thepoly(2-hydroxyethyl methacrylate)-based end blocks (A blocks) was about10,020 Daltons, corresponding to values of m˜77 and p˜77. The weightratio between the A blocks and the B blocks was about 10:80:10.Alternatively, if desired, the block copolymer can have the weight ratiobetween the A blocks and the B blocks of about 5:90:5. To obtain suchpolymer, those having ordinary skill in the art will choose anappropriate ratio between PBMA-XDC and HEMA in step 2 of the synthesisdescribed above in this example.

Example 5 Synthesis of an AB Block Copolymer (PSPMA-PBMA)

As a first step, a monomer BMA was dissolved in 2-butanone and aninitiator BDC was added. The amounts of components are summarized inTable 8.

TABLE 8 Amount of the component No. Component mmol g 1 BMA 140.8 20.0 22-butanone — 60.0 3 BDC 0.1 0.0239

The solution of BMA and BDC in 2-butanone was placed into a borosilicatevial, purged with dry nitrogen for about 30 minutes and the vial wassealed. The contents of vial were subjected to UV radiation at awavelength within a range of between about 310 nm and about 400 nm, forabout 12 hours. The vial was then opened and the contents were added, ina dropwise manner, to ethanol that was cooled to a temperature of about−76° C. As a result, poly(butylmethacrylate)-BDC (PBMA-BDC) wasprecipitated. The molecular weight of the PBMA-BDC was about 200,000Daltons as measured by GPC. The precipitate was collected using a vacuumfunnel and vacuum-dried.

As a second step, PBMA-BDC obtained as described above was combined with3-sulfopropylmethacrylate and a 2% (mass) solution of PEG having weightaverage molecular weight of about 750 in aqueous 2-butanone. The amountsof components are shown in Table 9.

TABLE 9 No. Component Weight fraction Amount, grams 1 PBMA-BDC 0.7515.00 2 3-sulfopropylmethacrylate 0.25 5.00 3 2% PEG in 2-butanone/water— 60.00

The blend of PBMA-BDC, 3-sulfopropylmethacrylate, and the PEG solutionin aqueous 2-butanone was placed into a borosilicate vial, purged withdry nitrogen for about 10 minutes and the vial was sealed. The contentsof vial were subjected to UV radiation at a wavelength within a range ofbetween about 310 nm and about 400 nm, for about 12 hours. The vial wasthen opened and the contents were added dropwise to water and vigorouslystirred causing precipitation of apoly(3-sulfopropylmethacrylate)-block-poly(butylmethacrylate)-BDC,having molecular weight of about 266,700 Daltons. The precipitate wascollected using a vacuum funnel and vacuum-dried followed by hydrolysisin the presence of a strong base to remove BDC. As a result of thedescribed process, an AB block copolymer,poly(3-sulfopropylmethacrylate)-block-poly(butylmethacrylate), wasprecipitated, the AB block copolymer having the general formula (XII):

The molecular weight of the PBMA-based blocks (B blocks) was about200,000 Daltons as measured by GPC corresponding to the value ofn˜1,400, the molecular weight of thepoly(3-sulfopropylmethacrylate)-based blocks (A blocks) was about 66,700Daltons, corresponding to values of m˜324. Overall molecular weight ofthe block copolymer was about 266,700 Daltons.

Example 6 Synthesis of a Random Copolymer #1 P(BMA-HEMA)

A solution was prepared by thoroughly mixing the following components:

(a) about 48.02 mass % BMA;

(b) about 5.33 mass % HEMA;

(c) about 1.60 mass % of initiator 2,2-dimethoxy-2-phenol acetophenone;and

(f) the balance, benzene.

An inert atmosphere was created by bubbling nitrogen gas through thesolution for about 30 minutes. The solution was then be exposed to UVradiation for about 10 minutes at a wavelength of 360 nm while beingcontinuously stirred causing formation of a random copolymer, poly(butylmethacrylate-co-2-hydroxyethyl methacrylate), P(BMA-HEMA).

The final P(BMA-HEMA) random copolymer was precipitated with anon-solvent such as hexane and vacuum dried. The copolymer had a massratio between the units derived from BMA and the units derived from HEMAof about 90:10. Alternatively, if desired, the copolymer can have themass ratio between the units derived from BMA and the units derived fromHEMA of about 80:20. To obtain such copolymer, those having ordinaryskill in the art will choose an appropriate ratio between BMA and HEMAin the synthesis described above in this Example.

Example 7 Synthesis of a Random Copolymer #2 P(MMA-BMA-AA-PEGA)

A solution can be prepared by thoroughly mixing the followingcomponents:

(a) about 15 mass % MMA;

(b) about 9 mass % BMA;

(c) about 8 mass % PEG-acrylate (PEGA), where PEG can haveweight-average molecular weight of about 6,000;

(d) about 20 mass % acrylic acid (AA);

(e) about 3 mass % initiator 2,2-dimethoxy-2-phenol acetophenone; and

(f) the balance, benzene.

An inert atmosphere can be created by bubbling nitrogen gas through thesolution for about 30 minutes. The solution can then be exposed to UVradiation for about 10 minutes at a wavelength of 360 nm while beingcontinuously stirred causing formation of a random copolymer,P(MMA-BMA-AA-PEGA).

The final P(MMA-BMA-AA-PEGA) random copolymer can be precipitated with anon-solvent such as hexane and vacuum dried. The copolymer can then bemixed with EVAL in a mass ratio of about 2:3 and the mixture can beapplied onto a stent to form a reservoir layer or a topcoat layer.

Example 8

A first composition was prepared by mixing the following components:

(a) about 2.0 mass % BIOSPAN polymer; and

(b) the balance, a solvent blend containing dimethylacetamide (DMAC) andpentane, the mass ratio between DMAC and pentane in the blend was about4:1.

The first composition was applied onto the surface of a bare 13 mm TETRAstent (available from Guidant Corporation) by spraying and dried to forma primer layer. A spray coater was used having a 0.014 fan nozzlemaintained at about 60° C. with a feed pressure of about 0.2 atm (about3 psi) and an atomization pressure of about 1.3 atm (about 20 psi). Theprimer was baked at about 80° C. for about 1 hour, yielding a dry primerlayer. The dry primer layer contained about 100 μg of BIOSPAN polymer.

A second composition was prepared by mixing the following components:

(a) about 1.8 mass % BIOSPAN polymer;

(b) about 0.2 mass % c-RGD; and

(c) the balance, a solvent blend containing DMAC and pentane, the massratio between DMAC and pentane in the blend was about 4:1.

The mass ratio between c-RGD and the BIOSPAN polymer in the secondcomposition was about 1:9. Overall, the second composition contained thetotal of about 600 μg of the BIOSPAN/c-RGD mixture. The secondcomposition was applied onto the dried primer layer to form thereservoir layer, using the same spraying technique and equipment usedfor applying the primer layer, followed by drying, i.e., by baking atabout 50° C. for about 2 hours, yielding a dry reservoir layer.

Example 9

A first composition was prepared by mixing the following components:

(a) about 2.0 mass % PBMA; and

(b) the balance, a solvent blend of acetone and cyclohexanone in a massratio of about 7:3.

The first composition was applied onto the surface of a bare 13 mm TETRAstent, using technique described in Example 8. The primer was baked atabout 80° C. for about 30 minutes, yielding a dry primer layer. The dryprimer layer contained about 60 μg of PBMA.

A second composition was prepared by mixing the following components:

(a) about 1.8 mass % BIOSPAN polymer;

(b) between about 0.2 mass % c-RGD; and

(c) the balance, a solvent blend containing DMAC and pentane, the massratio between DMAC and pentane in the blend was about 4:1.

The mass ratio between c-RGD and the BIOSPAN polymer in the secondcomposition was about 1:9. Overall, the second composition contained thetotal of about 500 μg of the BIOSPAN/c-RGD mixture. The secondcomposition was applied onto the dried primer layer to form thereservoir layer, using the same spraying technique and equipment usedfor applying the primer layer, followed by drying, i.e., by baking atabout 80° C. for about 30 minutes, yielding a dry reservoir layer.

A third composition was prepared by mixing the following components:

(a) about 2.0 mass % SOLEF 21508 (“SOLEF”) polymer; and

(b) the balance, a solvent blend of acetone and cyclohexanone in a massratio of about 7:3.

SOLEF 21508 is a trade name of poly(vinylidenefluoride-co-hexafluoropropene) available from Solvay Fluoropolymers,Inc. of Houston, Tex. The third composition was applied onto the driedreservoir layer to form a topcoat layer, using the same sprayingtechnique and equipment used for applying the primer layer and thereservoir layer. The wet topcoat layer was dried and baked at about 50°C. for about 2 hours, yielding a dry topcoat layer. The dry topcoatlayer contained about 200 μg of the SOLEF polymer.

The coated stent was subjected to an in vitro mechanical test accordingto the following procedure. The stent was guided through a tortuous pathand then deployed in a poly(vinyl alcohol) (PVA) lesion havingapproximate size of about 3 by 10 millimeters. The tortuous path and thelesion contained de-ionized water at about 37° C. To deploy the stent,pressure of about 12 atm was applied to the balloon for about 1 minute,followed by deflating of the balloon and retraction of the catheter.After the catheter was retracted, de-ionized water was pumped throughthe tortuous path and the lesion for about 1 hour at a rate of about 50milliliters per minute. Water was maintained at about 37° C.

Overall views of the coated stent which underwent the simulated in-vitrotesting are shown by the microphotographs on FIGS. 1A-1F. After thesimulated use test, the quality of the stent coatings was good. Nosubstantial porosity of the coating on the outer surface areas wasobserved. The damage of the coatings was only minimal, and themechanical integrity of the coating was preserved.

Example 10

The stent was coated as in Example 9, except the mass ratio betweenc-RGD and the BIOSPAN polymer in the second composition was about 1:6.Following the fabrication of the stent coating, the rate of release ofc-RGD from the stent was determined. The coated stent was immersed in anaqueous phosphate buffered saline solution, the solution was maintainedat a temperature of about 37° C., and the drug release was periodicallymeasured by the high pressure liquid chromatography (HPLC) method, whilethe temperature of the solution was maintained constant at about 37° C.As shown by the graph presented by FIG. 2, the rate of release for thestent having a SOLEF topcoat (curve 1) is substantially reduced comparedto the stent coating having no topcoat (curve 2).

Example 11

A primer was formed on a 13 mm TETRA stent as described in Example 9. Acomposition was prepared by mixing the following components:

(a) about 1.8 mass % BIOSPAN polymer;

(b) about 0.2 mass % c-RGD; and

(c) the balance, a solvent blend containing DMAC and pentane, the massratio between DMAC and pentane in the blend was about 4:1.

The mass ratio between c-RGD and the BIOSPAN polymer in the firstcomposition was about 1:9. Overall, the second composition contained thetotal of about 500 μg of the BIOSPAN/c-RGD mixture. The composition wasapplied onto the dried primer layer to form the reservoir layer, usingthe same spraying technique and equipment used for applying the primerlayer, followed by drying, i.e., by baking at about 80° C. for about 30minutes, yielding a dry reservoir layer.

Following the formation of the dry reservoir layer, a SOLEF-basedtopcoat layer was formed over the reservoir layer as described inExample 9. The stent coating was tested in vitro as described in Example9, and likewise showed good mechanical qualities while providing asustained release of c-RGD.

Example 12

A primer was formed on a 13 mm TETRA stent as described in Example 9. Afirst composition was prepared by mixing the following components:

(a) about 1.5 mass % PHEMA-PBMA-PHEMA ABA block-copolymer synthesized asdescribed in Example 4, the block copolymer containing about 90 mass %of PBMA blocks and about 5 mass % of each of the PHEMA blocks;

(b) about 0.5 mass % c-RGD; and

(c) the balance, a solvent blend of dimethylacetamide and methanol in amass ratio of about 7:3.

The mass ratio between c-RGD and the ABA block-polymer in the firstcomposition was about 1:3. Overall, the first composition contained thetotal of about 440 μg of the ABA block-copolymer/c-RGD mixture, whichmeans that about 110 μg of c-RGD was deposited onto the stent. The firstcomposition was applied onto the dried primer layer to form thereservoir layer, using the same spraying technique and equipment usedfor applying the primer layer, followed by drying, i.e., by baking atabout 80° C. for about 30 minutes, yielding a dry reservoir layer.

A second composition was prepared by mixing the following components:

(a) about 2.0 mass % PBMA; and

(b) the balance, a solvent blend of acetone and cyclohexanone in a massratio of about 7:3.

The second composition was applied onto the dried reservoir layer toform a topcoat layer, using the same spraying technique and equipmentused for applying the primer layer and the reservoir layer. The wettopcoat layer was dried and baked at about 80° C. for about 30 minutes,yielding a dry topcoat layer. The dry topcoat layer contained about 200μg of PBMA.

Example 13

A primer was formed on a 13 mm TETRA stent as described in Example 9. Acomposition was prepared by mixing the following components:

(a) about 1.8 mass % PHEMA-PBMA-PHEMA block-copolymer synthesized asdescribed in Example 4, the block copolymer containing about 90 mass %of PBMA blocks and about 5 mass % of each of the PHEMA blocks;

(b) about 0.2 mass % c-RGD; and

(c) the balance solvent blend of dimethylacetamide and methanol in amass ratio of about 7:3.

The mass ratio between c-RGD and the block-polymer in the firstcomposition was about 1:9. Overall, the composition contained the totalof about 500 μg of the block-copolymer/c-RGD mixture, which means thatabout 40 μg of c-RGD was deposited onto the stent.

The composition was applied onto the dried primer layer to form thereservoir layer, using the same spraying technique and equipment usedfor applying the primer layer, followed by drying, i.e., by baking atabout 80° C. for about 30 minutes, yielding a dry reservoir layer.

Example 14

A 13 mm TETRA stent was coated as described in Example 13. A compositionwas prepared by mixing the following components:

(a) about 2.0 mass % SOLEF polymer; and

(b) the balance, a solvent blend containing acetone and cyclohexanone,the mass ratio between acetone and pentane in the blend was about 7:3.

The composition was applied onto the dried reservoir layer to form atopcoat layer.

Example 15

The rate of release of c-RGD from the stents coated as described inExamples 13 and 14 was determined using the HPLC technique as describedin Example 9. The results are shown by FIG. 3. As can be seen from theresults presented by FIG. 3, the rate of release for the stent having aSOLEF topcoat (curve 3) is substantially reduced compared to the stentcoating having no topcoat (curve 4), especially in the initial stages ofthe release. Clearly, the stent coating having no topcoat does notcontrol the release of c-RGD.

Example 16

A first composition was prepared by mixing the following components:

(a) about 2.0 mass % PBMA; and

(b) the balance, a solvent blend of acetone and cyclohexanone in a massratio of about 7:3.

The first composition was applied onto the surface of a bare 12 mmVISION stent (available from Guidant Corp.), using technique describedin Example 8. The primer was baked at about 80° C. for about 30 minutes,yielding a dry primer layer. The dry primer layer contained about 100 μgof PBMA.

A second composition was prepared by mixing the following components:

(a) about 1.8 mass % BIOSPAN polymer;

(b) between about 0.2 mass % c-RGD; and

(c) the balance, a solvent blend containing DMAC and pentane, the massratio between DMAC and pentane in the blend was about 4:1.

The mass ratio between c-RGD and the BIOSPAN polymer in the secondcomposition was about 1:9. Overall, the second composition contained thetotal of about 500 μg of the BIOSPAN/c-RGD mixture. The secondcomposition was applied onto the dried primer layer to form thereservoir layer, using the same spraying technique and equipment usedfor applying the primer layer, followed by drying, i.e., by baking atabout 80° C. for about 30 minutes, yielding a dry reservoir layer.

A third composition was prepared by mixing the following components:

(a) about 2.0 mass % SOLEF polymer; and

(b) the balance, a solvent blend containing acetone and cyclohexanone,the mass ratio between acetone and cyclohexanone in the blend was about7:3.

The third composition was applied onto the dried reservoir layer to forma topcoat layer, using the same spraying technique and equipment usedfor applying the primer layer and the reservoir layer. The wet topcoatlayer was dried and baked at about 80° C. for about 30 minutes, yieldinga dry topcoat layer. The dry topcoat layer contained about 200 μg of theSOLEF polymer.

The coated stent was subjected to an in vitro mechanical test accordingto the procedure described in Example 9. Overall view of the coatedstent which underwent the simulated in vitro testing is shown by themicrophotograph of FIG. 4. After the simulated use test, the quality ofthe stent coating was good. No substantial porosity of the coating onthe outer surface areas was observed. The damage of the coatings wasonly minimal, and the mechanical integrity of the coating was preserved.

Example 17

A first composition was prepared by mixing the following components:

(a) about 2.0 mass % PBMA; and

(b) the balance, a solvent blend of acetone and cyclohexanone in a massratio of about 7:3.

The first composition was applied onto the surface of a bare 12 mmVISION stent, using technique described in Example 8. The primer wasbaked at about 80° C. for about 30 minutes, yielding a dry primer layer.The dry primer layer contained about 100 μg of PBMA.

A second composition was prepared by mixing the following components:

(a) about 1.714 mass % PHEMA-PBMA-PHEMA ABA block-copolymer synthesizedas described in Example 4, the block copolymer containing about 90 mass% of PBMA blocks and about 5 mass % of each of the PHEMA blocks;

(b) about 0.286 mass % c-RGD; and

(c) the balance, a solvent blend of dimethylacetamide and methanol in amass ratio of about 7:3.

The mass ratio between c-RGD and the ABA block-polymer in the secondcomposition was about 1:6. Overall, the second composition contained thetotal of about 500 μg of the ABA block-copolymer/c-RGD mixture. Thesecond composition was applied onto the dried primer layer to form thereservoir layer, using the same spraying technique and equipment usedfor applying the primer layer, followed by drying, i.e., by baking atabout 80° C. for about 30 minutes, yielding a dry reservoir layer.

A third composition was prepared by mixing the following components:

(a) about 2.0 mass % SOLEF polymer; and

(b) the balance, a solvent blend of acetone and cyclohexanone in a massratio of about 7:3.

The third composition was applied onto the dried reservoir layer to forma topcoat layer, using the same spraying technique and equipment usedfor applying the primer layer and the reservoir layer. The wet topcoatlayer was dried and baked at about 80° C. for about 30 minutes, yieldinga dry topcoat layer. The dry topcoat layer contained about 200 μg of theSOLEF polymer.

The coated stent was subjected to an in-vitro mechanical test accordingto the procedure described in Example 9. Overall view of the coatedstent which underwent the simulated in-vitro testing is shown by themicrophotograph on FIG. 5. After the simulated use test, the quality ofthe stent coating was acceptable.

The rate of release of c-RGD from the stent coated as described abovewas also determined using the HPLC technique described in Example 9. Twoseparate stents coated as described above were tested. One test wasexpanded and another was not expanded. As shown by the graph presentedby FIG. 6, the rate of release for the stent having a SOLEF topcoat wassatisfactory, for the stent coating on both the expanded stent (curve 5)and the unexpanded stent (curve 6).

The compositions of the coatings described in Examples 8-14, 16, and 17are summarized in Table 10.

TABLE 10 Reservoir Composition (1) P*⁾ D:P Example Stent Type Primer (2)D*⁾ Ratio*⁾ Topcoat 8 13 mm TETRA BIOSPAN (1) BIOSPAN 1:9 None (2) c-RGD9 13 mm TETRA PBMA (1) BIOSPAN 1:9 SOLEF (2) c-RGD 10 13 mm TETRA PBMA(1) BIOSPAN 1:6 SOLEF (2) c-RGD 11 13 mm TETRA PBMA (1) BIOSPAN 1:9SOLEF (2) c-RGD 12 13 mm TETRA PBMA (1) PHEMA-PBMA-PHEMA 1:3 PBMA (2)c-RGD 13 13 mm TETRA PBMA (1) PHEMA-PBMA-PHEMA 1:9 None (2) c-RGD 14 13mm TETRA PBMA (1) PHEMA-PBMA-PHEMA 1:9 SOLEF (2) c-RGD 16 12 mm VISIONPBMA (1) BIOSPAN 1:9 SOLEF (2) c-RGD 17 12 mm VISION PBMA (1)PHEMA-PBMA-PHEMA 1:6 SOLEF (2) c-RGD *⁾D = Drug; P = Polymer

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

What is claimed is:
 1. A medical article, comprising an implantablesubstrate and a polymer coating disposed at least on a portion of thesubstrate, the coating comprises a primer layer and a reservoir layer,wherein the reservoir layer includes a segmented polyurethane comprisinga soft segment and a hard segment; wherein the soft segment is derivedfrom a polyol and the hard segment is derived from an isocyanate,wherein the polymer coating further includes a hydrophilic therapeuticagent selected from the group consisting of cyclic-RGD peptide,poly(L-arginine), poly(D-arginine), poly(D,L-arginine), poly(L-lysine),poly(D-lysine), poly(δ-guanidino-α-aminobutyric acid), a racemic mixtureof poly(L-arginine) with poly(D-arginine), elastin mimetic polypeptides,and combinations thereof, wherein the hydrophilic therapeutic agent andthe segmented polyurethane has a mass ratio that is between about 1:10and about 1:3; wherein the primer layer comprises an acrylic polymer. 2.The medical article of claim 1, wherein the substrate is a stent.
 3. Themedical article of claim 1, wherein the isocyanate comprises aromaticdiisocyanates, cycloaliphatic diisocyanates, or aliphatic diisocyanates.4. The medical article of claim 3, wherein the aromatic diisocyanate isselected from 2,4-toluene diisocyanate and diphenylmethane diisocyanate.5. The medical article of claim 3, wherein the cycloaliphaticdiisocyanates are selected from a group consisting of 1,4-cyclohexanediisocyanate, methylene dicyclohexyl diisocyanate, 1,6-hexamethylenediisocyanate, and blends thereof.
 6. The medical article of claim 3,wherein the aliphatic diisocyanates are selected from a group consistingof 1,6-diisocyanato hexane and 1,6-diisocyanato dodecanc.
 7. The medicalarticle of claim 1, wherein the segmented polyurethane ispoly(urethane-urea), poly(ether urethane), or poly(carbonate urethane).8. The medical article of claim 1, wherein the segmented polyurethane isa poly(urethane-urea) and in the poly(urethane-urea) the soft segment isa moiety derived from poly(tetramethylene glycol) and the hard segmentis a moiety derived from diphenylmethane diisocyanate.
 9. The medicalarticle of claim 1, wherein the segmented polyurethane comprises adiamine as chain extender.
 10. The medical article of claim 9, whereinthe diamine is selected from the group consisting of 1,4-butanediamine,1,5-pentanediamine, 1,3-diaminocyclohexane, 1,4-diaminocycloxexane, anda combination thereof.
 11. The medical article of claim 1, wherein thecoating further comprises an agent that forms pores in the coating. 12.The medical article of claim 11, wherein the agent that forms pores isselected from the group consisting of low molecular weight poly(ethyleneglycol), poly(N-vinyl pyrrolidone), sugars, and sodium phosphate. 13.The medical article of claim 1, wherein the coating further comprises astabilizing additive.
 14. The medical article of claim 13, whereinstabilizing additive is a poly(methacrylate), or an antioxidant.
 15. Themedical article of claim 1, wherein the segmented polyurethane has theformula of

wherein n is a positive integer, and x is an integer about
 40. 16. Themedical article of claim 1, wherein the polyol is selected from a groupconsisting of poly(ethylene glycol), poly(propylene glycol),poly(tetramethylene glycol), poly(ethylene glycol-co-propylene glycol),poly(ethylene oxide-co-propylene oxide), and blends thereof.
 17. Themedical article of claim 1, wherein the segmented polyurethane is apoly(urethane-urea).
 18. A medical article, comprising an implantablesubstrate and a polymer coating disposed at least on a portion of thesubstrate, the coating includes a segmented polyurethane comprising asoft segment and a hard segment; wherein the soft segment is derivedfrom a polyol and the hard segment is derived from an isocyanate,wherein the polymer coating further includes a hydrophilic therapeuticagent selected from the group consisting of cyclic-RGD peptide,poly(L-arginine), poly(D-arginine), poly(D,L-arginine), poly(L-lysine),poly(D-lysine), poly(δ-guanidino-α-aminobutyric acid), a racemic mixtureof poly(L-arginine) with poly(D-arginine), elastin mimetic polypeptides,and combinations thereof, wherein the hydrophilic therapeutic agent andthe segmented polyurethane has a mass ratio that is between about 1:10and about 1:3; wherein the coating comprises a reservoir layer and a toplayer; wherein the top layer comprises a vinyl halide polymer orcopolymer.
 19. The medical article of claim 18, wherein the substrate isa stent.
 20. The medical article of claim 18, wherein the isocyanatecomprises aromatic diisocyanates, cycloaliphatic diisocyanates, oraliphatic diisocyanates.
 21. The medical article of claim 20, whereinthe aromatic diisocyanate is selected from 2,4-toluene diisocyanate anddiphenylmethane diisocyanate.
 22. The medical article of claim 20,wherein the cycloaliphatic diisocyanates are selected from a groupconsisting of 1,4-cyclohexane diisocyanate, methylene dicyclohexyldiisocyanate, 1,6-hexamethylene diisocyanate, and blends thereof. 23.The medical article of claim 20, wherein the aliphatic diisocyanates areselected from a group consisting of 1,6-diisocyanato hexane and1,6-diisocyanato dodecane.
 24. The medical article of claim 18, whereinthe segmented polyurethane is poly(urethane-urea), poly(ether urethane),or poly(carbonate urethane).
 25. The medical article of claim 18,wherein the segmented polyurethane is a poly(urethane-urea) and in thepoly(urethane-urea) the soft segment is a moiety derived frompoly(tetramethylene glycol) and the hard segment is a moiety derivedfrom diphenylmethane diisocyanate.
 26. The medical article of claim 18,wherein the segmented polyurethane comprises a diamine as chainextender.
 27. The medical article of claim 26, wherein the diamine isselected from the group consisting of 1,4-butanediamine,1,5-pentanediamine, 1,3-diaminocyclohexane, 1,4-diaminocycloxexane, anda combination thereof.
 28. The medical article of claim 18, wherein thecoating further comprises an agent that forms pores in the coating. 29.The medical article of claim 18, wherein the coating further comprises astabilizing additive.
 30. The medical article of claim 28, wherein theagent that forms pores is selected from the group consisting of lowmolecular weight poly(ethylene glycol), poly(N-vinyl pyrrolidone),sugars, and sodium phosphate.
 31. The medical article of claim 29,wherein stabilizing additive is a poly(methacrylate), or an antioxidant.32. The medical article of claim 18, wherein the segmented polyurethanehas the formula of

wherein n is a positive integer, and x is an integer about
 40. 33. Themedical article of claim 18, wherein the polyol is selected from a groupconsisting of poly(ethylene glycol), poly(propylene glycol),poly(tetramethylene glycol), poly(ethylene glycol-co-propylene glycol),poly(ethylene oxide-co-propylene oxide), and blends thereof.
 34. Themedical article of claim 18, wherein the segmented polyurethane is apoly(urethane-urea).